Calcium homeostasis

Bone remodeling and repair

• Continuous remodeling– 5 to 7 % of total bone mass per week– Critical for maintenance of proper structure

• Removal of calcium

Bone remodeling

• Location– Periosteum– Endosteum

• Remodeling units– Osteoblasts– Osteoclasts

• Does not occur uniformly– Different bones/different rates

Bone remodeling

• Deposit– Site of injury– Strength re-enforcement– Nutrients

• Proteins• Vitamins (A and D)• Minerals

Bone remodeling

• Deposit– Osteroid seam

• New matrix deposit– Unmineralized bone

• Calcification front• Rate of calcification

– Local concentrations of mineral products– Matrix proteins– Alkaline phosphatase

Bone remodeling

• Resorption– Break down of bone matrix

• Formation of resorption bay

– Osteoclasts• Lysosomal enzymes• HCL• Phagocytosis of dead osteocytes• Activation triggered by T-lymphocytes

• Regulation– Feedback loops

(Whether and when)• Calcium homeostasis in

the blood• Parathyroid hormone

(PTH)– Elevates blood calcium

concentration by increasing resorption

• Calcitonin– Increase calcium

deposition by osteoblasts

Parathyroid gland

• Embedded on the thyroid surface– Four in humans

• Located in the back of thyroid glands

• Removal of thyroid gland– Lethal

• Removal of parathyroid glands

– Decrease in blood calcium level

• Tetanic convulsion and death

• Cell composition– Chief cells

• Secretes parathyroid hormone

– Oxyphil cells• Unknown functions

Oxyphil cells

Parathyroid hormone

• Essential for life

• Chemistry– 84 AA

• Preprohormone (115 AA)– Synthesized and converted within the Golgi zone of the

chief cells– Proteolytic cleavage yields 90 AA prohormone

• prohormone– Removal of 6 AA to yield mature peptide

• Released into the bloodstream via exocytosis

• Highly conserved hormone

• Short half-life– 3-4 min– Cleaved into two fragments

Regulation of secretion• Blood calcium level

– Ca receptors on the parathyroid cells• Seven-transmembrane domain receptor

– Coupled with G-protein complex

• Highly conserved– 93 % AA homology between human and bovine

receptors

• Interaction of receptor with Ca– Concentration- dependent conformation alteration– Decreased cAMP production when high Ca

concentrations– Increased cAMP production when low Ca concentrations

• Vitamin D– Inhibition of PTH secretion

• Genomic level• Slow effects

– No changes in release of PTH immediately after vitamin D treatment

Function of PTH

• Elevation of blood calcium level– Decreased phosphate ion concentrations– Acts on kidneys, intestines, and bones

• Effects on mineral metabolism– Increased osteoclast activity

• Secretion of cytokines by stromal osteoblast in response to PTH

• Demineralization of bones

• Renal excretion and reabsorption– Increased calcium reabsporption

• Renal tubular reabsorption

– Increased phosphate excretion (phosphaturia)

• Increased ionization of calcium– Prevention of CaPO4 formation

– Increased Mg reabsorption– Inhibition of Na-H exchange

• Decreased blood pH – Inhibition of Ca binding to plasma proteins

• Absorption of calcium– Intestine

• Increased uptake (direct)• Effects on vitamin D metabolism (indirect)

• Control of vitamin D synthesis– Increased 1,25-dihydrovitamin D synthesis

from vitamin D• Kidney

• Other actions– Increased reticulocyte and lymphocyte

mitosis– Vasodilation

• Direct action involving specific receptor

Mechanism of action• Interaction between

PTH and its receptor– Increased cAMP

production• Gs

– Activation of phospholipase C

• Production of IP3 and DG– Activated by Gq

– Vitamin D-dependent• Mobilization of Ca from

bones

• Role of vitamin D on PTH action– Not on cAMP production

• Normal cAMP production by the bones from vitamin D deficient mice

– Later parts of biochemical reactions

Calcitonin• Maintenance of blood

Ca level– Critical– Acute elevation

• Meal– Return to normal

shortly after elevation

• Role of thyroid gland– Secretion of calcitonin

• C (clear) cells

Synthesis and metabolism• 32 AA

– Derived from larger prohormone

– Ring structure• Disulfide bridge

between AA 1 and AA 7

• Isoforms– Two

• I in combination with II or III

• High structural similarity– Low AA homology– Fish calcitonin is more potent in humans

• Resists proteolytic digestion• Higher receptor affinity